Over the past year we have pursued studies on B lymphocyte immunopathogenesis in HIV disease by focusing on 1) antigen-specific B cell effector and memory responses in HIV-infected individuals; 2) phenotypic and functional correlates of B cell dysfunction in the setting of advancing HIV disease; 3) mechanisms of HIV virion trapping in lymphoid tissues; and 4) mechanisms of B cell death associated with HIV disease. The first study describing the loss of antigen-specific B cell responses in the setting of HIV disease has recently been completed. This project, undertaken as a large clinical study aimed at evaluating B cell responses to influenza vaccination, compared influenza-specific effector and memory B cell responses, as well as antibody titers in HIV-infected and HIV-negative individuals. By comparing influenza-specific effector and memory B cell responses, as well as antibody titers in HIV-infected and HIV-negative individuals, we found that all HIV-infected individuals, irrespective of disease status, had lower B cell memory responses compared to HIV-negative individuals, whereas defects in the effector and antibody responses were not as pronounced. Defects in anti-influenza B cell responses were found to correlate to CD4+ T cell count and to a lesser degree, HIV plasma viremia. In light of these findings and with stored samples accumulated from individuals representing a wide range of disease status, we explored new facets of B cell dysfunction in the setting of HIV disease. In doing so, we identified and characterized a new subset of B cells, defined by the expression of CD10, that were expanded in HIV-infected individuals with advancing disease. Phenotypic and functional characterization revealed these B cells to be immature, highly susceptible to apoptosis, unresponsive to most B-cell stimuli, and possibly arising as a result of IL-7-mediated homeostatic compensation in the setting of HIV-induced lymphopenia. This study has provided us with new insight into human B cell development and B cell dysfunction in HIV disease. In addition, we have pursued investigations of extracellular HIV reservoirs in a mouse model and have demonstrated that the complement receptor CD21 is essential for virion trapping in lymphoid tissues and that anti-CD21 antibodies that can displace HIV from CD21 positive cells have the potential for reducing viral burdens in vivo.